Antimicrobial Drugs. PowerPoint Lecture Presentations prepared by Bradley W. Christian, McLennan Community College C H A P T E R
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1 PowerPoint Lecture Presentations prepared by Bradley W. Christian, McLennan Community College C H A P T E R 20 Antimicrobial Drugs
2 The History of Chemotherapy Selective toxicity: selectively finding and destroying pathogens without damaging the host Chemotherapy: the use of chemicals to treat a disease Antibiotic: a substance produced by a microbe that, in small amounts, inhibits another microbe Antimicrobial drugs: synthetic substances that interfere with the growth of microbes
3 The History of Chemotherapy 1928: Fleming discovered penicillin, produced by Penicillium 1932: Prontosil red dye used for streptococcal infections 1940: First clinical trials of penicillin Today there is a growing problem of antibiotic resistance
4 Table 20.1 Representative Sources of Antibiotics
5 Spectrum of Antimicrobial Activity Narrow spectrum of microbial activity: drugs that affect a narrow range of microbial types Broad-spectrum antibiotics: affect a broad range of gram-positive or gram-negative bacteria Superinfection: overgrowth of normal microbiota that is resistant to antibiotics
6 Table 20.2 The Spectrum of Activity of Antibiotics and Other Antimicrobial Drugs
7 The Action of Antimicrobial Drugs Bactericidal Kill microbes directly Bacteriostatic Prevent microbes from growing
8 Figure 20.2 Major Action Modes of Antibacterial Drugs.
9 The Action of Antimicrobial Drugs Inhibiting cell wall synthesis Penicillins prevent the synthesis of peptidoglycan
10 Figure 20.3 The inhibition of bacterial cell wall synthesis by penicillin.
11 The Action of Antimicrobial Drugs Inhibiting protein synthesis Target bacterial 70S ribosomes Chloramphenicol, erythromycin, streptomycin, tetracyclines
12 Figure 20.4 The inhibition of protein synthesis by antibiotics. 5' Protein synthesis site 50S Growing polypeptide Tunnel Growing polypeptide Chloramphenicol Binds to 50S portion and inhibits formation of peptide bond 50S portion 30S 3' mrna Protein synthesis site Three-dimensional detail of the protein synthesis site showing the 30S and 50S subunit portions of the 70S prokaryotic ribosome trna Messenger RNA 30S portion Direction of ribosome movement Streptomycin Changes shape of 30S portion, causing code on mrna to be read incorrectly 70S prokaryotic ribosome Translation Tetracyclines Interfere with attachment of trna to mrna ribosome complex Diagram indicating the different points at which chloramphenicol, the tetracyclines, and streptomycin exert their activities
13 The Action of Antimicrobial Drugs Injuring the plasma membrane Polypeptide antibiotics change membrane permeability Antifungal drugs combine with membrane sterols
14 Figure 20.5 Injury to the plasma membrane of a yeast cell caused by an antifungal drug.
15 The Action of Antimicrobial Drugs Inhibiting nucleic acid synthesis Interfere with DNA replication and transcription Inhibiting the synthesis of essential metabolites Antimetabolites compete with normal substrates for an enzyme Sulfanilamide competes with para-aminobenzoic acid (PABA), stopping the synthesis of folic acid
16 Table 20.3 Antibacterial Drugs (1 of 2)
17 Table 20.3 Antibacterial Drugs (2 of 2)
18 Table 20.4 Differential Grouping of Cephalosporins
19 Table 20.5 Antifungal, Antiviral, Antiprotozoan, and Antihelminthic Drugs (1 of 2)
20 Table 20.5 Antifungal, Antiviral, Antiprotozoan, and Antihelminthic Drugs (2 of 2)
21 Antibacterial Antibiotics: Inhibitors of Cell Wall Synthesis Penicillin Contain a β-lactam ring Types are differentiated by the chemical side chains attached to the ring Prevent the cross-linking of peptidoglycans, interfering with cell wall construction (especially gram-positives)
22 Antibacterial Antibiotics: Inhibitors of Cell Wall Synthesis Natural penicillins Extracted from Penicillium cultures Penicillin G (injected) and Penicillin V (oral) Narrow spectrum of activity Susceptible to penicillinases (β-lactamases) Semisynthetic penicillins Contain chemically added side chains, making them resistant to penicillinases
23 Figure 20.6a The structure of penicillins, antibacterial antibiotics. Natural penicillins Common nucleus Penicillin G (requires injection) β-lactam ring Penicillin V (can be taken orally)
24 Figure 20.6b The structure of penicillins, antibacterial antibiotics. Semisynthetic penicillins Common nucleus Oxacillin: Narrow spectrum, only gram-positives, but resistant to penicillinase β-lactam ring Ampicillin: Extended spectrum, many gram-negatives
25 Figure 20.8 The effect of penicillinase on penicillins. β-lactam ring Penicillinase Penicillin Penicilloic acid
26 Antibacterial Antibiotics: Inhibitors of Cell Wall Synthesis Penicillinase-resistant penicillins Methicillin and oxacillin Extended-spectrum penicillins Effective against gram-negatives as well as grampositives Aminopenicillins: ampicillin, amoxicillin Penicillins plus β-lactamase inhibitors Contain clavulanic acid, a noncompetitive inhibitor of penicillinase
27 Antibacterial Antibiotics: Inhibitors of Cell Wall Synthesis Carbapenems Substitute a C for an S and add a double bond to the penicillin nucleus Broad spectrum Primaxin, doripenem Monobactam Synthetic; single ring instead of the β-lactam double ring Low toxicity; works against only certain gram-negatives Aztreonam
28 Antibacterial Antibiotics: Inhibitors of Cell Wall Synthesis Cephalosporins Work similar to penicillins β-lactam ring differs from penicillin Grouped according to their generation of development Polypeptide antibiotics Bacitracin Topical application; works against gram-positives Vancomycin Glycopeptide Last line against antibiotic-resistant MRSA
29 Figure 20.9 The nuclear structures of cephalosporin and penicillin compared. β-lactam ring Cephalosporin nucleus Penicillin nucleus
30 Antimycobacterial Antibiotics Isoniazid (INH) Inhibits the mycolic acid synthesis in mycobacteria Ethambutol Inhibits incorporation of mycolic acid into the cell wall
31 Chloramphenicol Inhibits peptide bond formation Binds to the 50S subunit of the 70S ribosome Synthesized chemically; broad spectrum Can suppress bone marrow and affect blood cell formation
32 Figure The structure of the antibacterial antibiotic chloramphenicol.
33 Aminoglycosides Amino sugars linked by glycoside bonds Change the shape of the 30S subunit of the 70S ribosome Can cause auditory damage Streptomycin, neomycin, gentamicin
34 Tetracyclines Produced by Streptomyces spp. Interfere with the trna attachment to the ribosome Broad spectrum; penetrate tissues, making them valuable against rickettsias and chlamydias Can suppress normal intestinal microbiota
35 Figure The structure of the antibacterial antibiotic tetracycline.
36 Inhibitors of Protein Synthesis Glycylcyclines Broad spectrum; bacteriostatic Bind to the 30S ribosomal subunit Inhibits rapid efflux; administered intravenously Useful against MRSA Macrolides Contain a macrocyclic lactone ring Narrow spectrum against gram-positives Erythromycin
37 Figure The structure of the antibacterial antibiotic erythromycin, a representative macrolide. Macrocyclic lactone ring Erythromycin
38 Inhibitors of Protein Synthesis Streptogramins Attach to the 50S subunit Work against gram-positives that are resistant to other antibiotics Oxazolidinones Bind to the 50S/30S subunit interface Synthetic; combat MRSA (linezolid) Pleuromutilins Retapamulin: topical and effective against grampositives
39 Injury to the Plasma Membrane Affects synthesis of bacterial plasma membranes Lipopeptide Daptomycin Produced by streptomycetes; used for skin infections Attacks the bacterial cell membrane Polymyxin B Topical; bacteriocidal; effective against gram-negatives Combined with bacitracin and neomycin in nonprescription ointments
40 Nucleic Acid Synthesis Inhibitors Rifamycin Inhibits mrna synthesis Penetrates tissues; antitubercular activity Quinolone and fluoroquinolones Nalidixic acid Synthetic; inhibits DNA gyrase Norfloxacin and ciprofloxacin Broad spectrum; relatively nontoxic
41 Sulfonamides Inhibit the folic acid synthesis needed for nucleic acid and protein synthesis Competitively bind to the enzyme for PABA production, a folic acid precursor Combination of trimethoprim and sulfamethoxazole (TMP-SMZ) is an example of drug synergism
42 Figure Actions of the antibacterial synthetics trimethoprim and sulfamethoxazole.
43 Antifungal Drugs Agents affecting fungal sterols Interrupt the synthesis of ergosterol, making the membrane excessively permeable Polyenes Amphotericin B: produced by Streptomyces; toxic to the kidneys Azoles Imidazoles: topical; treat cutaneous mycoses Triazole: treat systemic fungal infections Allylamines For azole-resistant infections
44 Antifungal Drugs Agents affecting fungal cell walls Echinocandins Inhibit the synthesis of -glucan Agents inhibiting nucleic acids Flucytosine Cytosine analog interferes with RNA synthesis
45 Antiviral Drugs Entry and fusion inhibitors Block the receptors on the host cell that bind to the virus Block fusion of the virus and cell Uncoating, genome integration, and nucleic acid synthesis inhibitors Prevent viral uncoating Inhibit viral DNA integration into the host genome Nucleoside analogs inhibit RNA or DNA synthesis
46 Figure 20.16a The structure and function of the antiviral drug acyclovir.
47 Figure 20.16b-c The structure and function of the antiviral drug acyclovir.
48 Antiviral Drugs Interference with assembly and release of viral particles Protease inhibitors Block the cleavage of protein precursors Exit inhibitors Inhibit neuraminidase, an enzyme required for some viruses to bud from the host cell
49 Interferons Produced by viral-infected cells to inhibit further spread of the infection Imiquimod Promotes interferon production
50 Antivirals for Treating HIV/AIDS Antiretroviral Nucleoside analog (zidovudine) Nucleotide analog (tenofovir) Non-nucleoside inhibitors (nevirapine) Protease inhibitors (atazanavir) Integrase inhibitors (raltegravir) Entry inhibitors (miraviroc) Fusion inhibitors (enfuvirtide)
51 Antiprotozoan and Antihelminthic Drugs Antiprotozoan drugs Quinine and chloroquine Treat malaria Artemisinin Kills Plasmodium that causes malaria Metronidazole (Flagyl) Also interferes with anaerobic bacteria Treats Trichomonas, giardiasis, and amebic dysentery
52 Antiprotozoan and Antihelminthic Drugs Antihelminthic drugs Niclosamide Prevents ATP production Treats tapeworms Praziquantel Alters membrane permeability Treats tapeworms and flukes Mebendazole and albendazole Interfere with nutrient absorption Treat intestinal helminths Ivermectin Paralysis of helminths Treats roundworms and mites
53 The Diffusion Methods Disk-diffusion method (Kirby-Bauer test) Tests the effectiveness of chemotherapeutic agents Paper disks with a chemotherapeutic agent are placed on agar containing the test organism Zone of inhibition around the disk determines the sensitivity of the organism to the antibiotic
54 Figure The disk-diffusion method for determining the activity of antimicrobials.
55 The Diffusion Methods E test Determines the minimal inhibitory concentration (MIC) Lowest antibiotic concentration preventing bacterial growth
56 Figure The E test (for epsilometer), a gradient diffusion method that determines antibiotic sensitivity and estimates minimal inhibitory concentration (MIC). MIC
57 Broth Dilution Tests Determine the MIC and minimal bactericidal concentration (MBC) of an antimicrobial drug Test organism is placed into the wells of a tray containing dilutions of a drug; growth is determined Antibiograms Reports that record the susceptibility of organisms encountered clinically
58 Figure A microdilution, or microtiter, plate used for testing for minimal inhibitory concentration (MIC) of antibiotics. Highest Concentration of drug on plates Lowest Doxycycline (White spots show growth in all wells; bacterium is resistant) Sulfamethoxazole (Trailing end point; usually read where there is an estimated 80% reduction in growth) Streptomycin (No growth in any well; bacterium is sensitive at all concentrations) Ethambutol (Growth in fourth wells; bacterium is equally sensitive to ethambutol and kanamycin) Kanamycin
59 Resistance to Antimicrobial Drugs Persister cells: microbes with genetic characteristics allowing for their survival when exposed to an antibiotic Superbugs: bacteria that are resistant to large numbers of antibiotics Resistance genes are often spread horizontally among bacteria on plasmids or transposons via conjugation or transduction
60 Mechanisms of Resistance Enzymatic destruction or inactivation of the drug Prevention of penetration to the target site within the microbe Alteration of the drug's target site Rapid efflux (ejection) of the antibiotic Variations of mechanisms of resistance
61 Figure Bacterial Resistance to Antibiotics. 1. Blocking entry Antibiotic 3. Alteration of target molecule Antibiotic Altered target molecule Antibiotic Enzymatic action 4. Efflux of antibiotic 2. Inactivation by enzymes Inactivated antibiotic KEY CONCEPTS There are only a few mechanisms of microbial resistance to antimicrobial agents: blocking the drug's entry into the cell, inactivation of the drug by enzymes, alteration of the drug's target site, efflux of the drug from the cell, or alteration of the metabolic pathways of the host. The mechanisms of bacterial resistance to antibiotics are limited. Knowledge of these mechanisms is critical for understanding the limitations of antibiotic use.
62 Figure The development of an antibiotic-resistant mutant during antibiotic therapy. Initiation of antibiotic therapy Antibiotic resistance of bacterial population measured by amount of antibiotic needed to control growth Bacteria count
63 Effects of Combinations of Drugs Synergism: the effect of two drugs together is greater than the effect of either alone Antagonism: the effect of two drugs together is less than the effect of either alone
64 Figure An example of synergism between two different antibiotics. Area of synergistic inhibition, clear Area of growth, cloudy Disk with antibiotic amoxicillin-clavulanic acid Disk with antibiotic aztreonam
65 Future of Chemotherapeutic Agents Target virulence factors Sequester iron, which feeds pathogens Antimicrobial peptides produced by various organisms Phage therapy Bacteriocins: antimicrobial peptides produced by bacteria
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